Two major inositol transporters and their role in cryptococcal virulence. Wang Yina,Liu Tong-bao,Delmas Guillaume,Park Steven,Perlin David,Xue Chaoyang Eukaryotic cell Cryptococcus neoformans is an AIDS-associated human fungal pathogen and the most common cause of fungal meningitis, with a mortality rate over 40% in AIDS patients. Significant advances have been achieved in understanding its disease mechanisms. Yet the underlying mechanism of a high frequency of cryptococcal meningitis remains unclear. The existence of high inositol concentrations in brain and our earlier discovery of a large inositol transporter (ITR) gene family in C. neoformans led us to investigate the potential role of inositol in Cryptococcus-host interactions. In this study, we focus on functional analyses of two major ITR genes to understand their role in virulence of C. neoformans. Our results show that ITR1A and ITR3C are the only two ITR genes among 10 candidates that can complement the growth defect of a Saccharomyces cerevisiae strain lacking inositol transporters. Both S. cerevisiae strains heterologously expressing ITR1A or ITR3C showed high inositol uptake activity, an indication that they are major inositol transporters. Significantly, itr1a itr3c double mutants showed significant virulence attenuation in murine infection models. Mutating both ITR1A and ITR3C in an ino1 mutant background activates the expression of several remaining ITR candidates and does not show more severe virulence attenuation, suggesting that both inositol uptake and biosynthetic pathways are important for inositol acquisition. Overall, our study provides evidence that host inositol and fungal inositol transporters are important for Cryptococcus pathogenicity. 10.1128/EC.00327-10

Recent progress on antifungal drug development. Zhai Bing,Lin Xiaorong Current pharmaceutical biotechnology Invasive fungal infections are a serious threat to public health, particularly to people with compromised or suppressed immunity. Although the current antifungal therapies have been significantly improved, the outcome is still far from satisfactory, partly due the limited number of classes of clinically available antifungals, the development of resistance to current antifungals, and the challenges of proper and early diagnosis. Recent advances in the development of new antifungals, although still in the investigational stages, offer some new hope of improving the future of antifungal therapy. Here, we review literature regarding the antifungal activities of several FDA-approved drugs, which were originally intended for treating other conditions, as well as newly discovered natural/artificial compounds. We focus on their mechanisms of action, limitations, and potential in treating fungal infections. The diverse mechanisms of action of these compounds summarized here can provide new directions for future endeavors on antifungal drug development.

Cryptococcus neoformans adapts to the host environment through TOR-mediated remodeling of phospholipid asymmetry. Nature communications Cryptococcus spp. are environmental fungi that first must adapt to the host environment before they can cause life-threatening meningitis in immunocompromised patients. Host CO concentrations are 100-fold higher than the external environment and strains unable to grow at host CO concentrations are not pathogenic. Using a genetic screening and transcriptional profiling approach, we report that the TOR pathway is critical for C. neoformans adaptation to host CO partly through Ypk1-dependent remodeling of phosphatidylserine asymmetry at the plasma membrane. We also describe a C. neoformans ABC/PDR transporter (PDR9) that is highly expressed in CO-sensitive environmental strains, suppresses CO-induced phosphatidylserine/phospholipid remodeling, and increases susceptibility to host concentrations of CO. Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct in C. neoformans compared to S. cerevisiae. Finally, host CO concentrations suppress the C. neoformans pathways that respond to host temperature (Mpk1) and pH (Rim101), indicating that host adaptation requires a stringent balance among distinct stress responses. 10.1038/s41467-023-42318-y

Effects of CO in fungi. Current opinion in microbiology Carbon dioxide supplies carbon for photosynthetic species and is a major product of respiration for all life forms. Inside the human body where CO is a by-product of the tricarboxylic acid cycle, its level reaches 5% or higher. In the ambient atmosphere, ∼.04% of the air is CO. Different organisms can tolerate different CO levels to various degrees, and experiencing higher CO is toxic and can lead to death. The fungal kingdom shows great variations in response to CO that has been documented by different researchers at different time periods. This literature review aims to connect these studies, highlight mechanisms underlying tolerance to high levels of CO, and emphasize the effects of CO on fungal metabolism and morphogenesis. 10.1016/j.mib.2024.102488

Fungal morphogenesis. Cold Spring Harbor perspectives in medicine Morphogenesis in fungi is often induced by extracellular factors and executed by fungal genetic factors. Cell surface changes and alterations of the microenvironment often accompany morphogenetic changes in fungi. In this review, we will first discuss the general traits of yeast and hyphal morphotypes and how morphogenesis affects development and adaptation by fungi to their native niches, including host niches. Then we will focus on the molecular machinery responsible for the two most fundamental growth forms, yeast and hyphae. Last, we will describe how fungi incorporate exogenous environmental and host signals together with genetic factors to determine their morphotype and how morphogenesis, in turn, shapes the fungal microenvironment. 10.1101/cshperspect.a019679